Curcumin Analog L48H37 Induces Apoptosis in Human Oral Cancer Cells by Activating Caspase Cascades and Downregulating the Inhibitor of Apoptosis Proteins through JNK/p38 Signaling.

L48H37 is a synthetic curcumin analog that has anticancer potentials. Here, we further explored the anticancer effect of L48H37 on oral cancer cells and its mechanistic acts. Cell cycle distribution was assessed using flow cytometric analysis. Apoptosis was elucidated by staining with PI/Annexin V and activation of the caspase cascade. Cellular signaling was explored using apoptotic protein profiling, Western blotting, and specific inhibitors. Our findings showed that L48H37 significantly reduced the cell viability of SCC-9 and HSC-3 cells, resulting in sub-G1 phase accumulation and increased apoptotic cells. Apoptotic protein profiling revealed that L48H37 increased cleaved caspase-3, and downregulated cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) in SCC-9 cells, and the downregulated cIAP1 and XIAP in both oral cancer cells were also demonstrated by Western blotting. Meanwhile, L48H37 triggered the activation of caspases and mitogen-activated protein kinases (MAPKs). The involvement of c-Jun N-terminal kinase (JNK) and p38 MAPK (p38) in the L48H37-triggered apoptotic cascade in oral cancer cells was also elucidated by specific inhibitors. Collectively, these findings indicate that L48H37 has potent anticancer activity against oral cancer cells, which may be attributed to JNK/p38-mediated caspase activation and the resulting apoptosis. This suggests a potential benefit for L48H37 for the treatment of oral cancer.

A common trajectory of gut microbiome development during the first month in healthy neonates with limited inter-individual environmental variations.

The early development of the gut microbiome is governed by multiple factors and has significantly long-term effects on later-in-life health. To minimize inter-individual variations in the environment, we determined developmental trajectories of the gut microbiome in 28 healthy neonates during their stay at a postpartum center. Stool samples were collected at three time points: the first-pass meconium within 24 h of life, and at 7 and 28 days of age. Illumina sequencing of the V3-V4 region of 16S rRNA was used to investigate microbiota profiles. We found that there was a distinct microbiota structure at each time point, with a significant shift during the first week. Proteobacteria was most abundant in the first-pass meconium; Firmicutes and Actinobacteria increased with age and were substituted as the major components. Except for a short-term influence of different delivery modes on the microbiota composition, early microbiome development was not remarkably affected by gravidity, maternal intrapartum antibiotic treatment, premature rupture of membranes, or postnatal phototherapy. Hence, our data showed a similar developmental trajectory of the gut microbiome during the first month in healthy neonates when limited in environmental variations. Environmental factors external to the host were crucial in the early microbiome development.

Curcumin and its Analogs and Carriers: Potential Therapeutic Strategies for Human Osteosarcoma.

Curcumin is a natural polyphenol phytochemical derived from turmeric with antioxidant, anti-inflammatory, and anticancer properties but is concerned about poor solubility in water, absorption, and metabolic stability. Potent metastatic osteosarcoma is the most common primary bone cancer in children, adolescents, and young adults. It is responsible for low survival rates because of its high rate of metastasis to the lungs. To improve poor bioavailability, numerous curcumin analogs were developed to possess anticancer characteristics through a variety of biological pathways involved in cytotoxicity, proliferation, autophagy, sensitizing chemotherapy, and metastases. This review provides an overview of their various pharmacological functions, molecular mechanisms, and therapeutic potential as a remedy for human osteosarcoma. To enhance therapeutic efficacy, several liposomal nanoparticles, nanocarriers, multifunctional micelles, and three-dimensional printed scaffolds have also been developed for the controlled delivery of curcumin targeting human osteosarcoma cells. Consequently, curcumin and several potential analogs and delivery formulations are optimistic candidates to improve the currently available strategy for human osteosarcoma. However, further insight into the mechanism of action of promising curcumin analogs and the development of carriers in clinical trials of osteosarcoma needs to be investigated to improve their overall potency and clinical utility, in particular the anti-metastatic effect.

Gambogic Acid Induces HO-1 Expression and Cell Apoptosis through p38 Signaling in Oral Squamous Cell Carcinoma.

Gambogic acid (GA), a natural and bioactive compound from the gamboge resin, has been reported to exhibit many oncostatic activities against several types of malignancies. However, its effects on the progression of oral squamous cell carcinoma (OSCC) remain largely unexplored. To fill this gap, we investigated the anticancer role of GA and molecular mechanisms underlying GA's actions in combating oral cancer. We found that GA negatively regulated the viability of OSCC cells, involving induction of the sub-G1 phase and cell apoptosis. In addition, a specific signature of apoptotic proteome, such as upregulation of heme oxygenase-1 (HO-1) and activation of caspase cascades, was identified in GA-treated OSCC. Moreover, such induction of HO-1 expression and caspase cleavage by GA was significantly diminished through the pharmacological inhibition of p38 kinase. In conclusion, these results demonstrate that GA promotes cell apoptosis in OSCC, accompanied with the activation of a p38-dependent apoptotic pathway. Our findings provide potential avenues for the use of GA with high safety and therapeutic implications in restraining oral cancer.

Asiatic acid from centella asiatica exert anti-invasive ability in human renal cancer cells by modulation of ERK/p38MAPK-mediated MMP15 expression.

BACKGROUND: Asiatic acid (AA) is a naturally pentacyclic triterpenoids extracted from traditional medicine Centella asiatica l. that has demonstrated possesses potential health benefits and antitumor ability. However, the precise anticancer effects and mechanisms by which AA impact RCC cells remains unclear. METHODS: Cell proliferation and cell cycle distribution were detected by MTT, colony formation assay and PI stain by flow cytometry, respectively. Cell mobility and invasiveness were determined by in vitro migration and invasion assay. The secretory MMP15 was detected by ELISA assay. Quantitative RT-PCR, siRNA, and immunoblot were used to determine gene expression/regulation and protein expression, respectively. Antimetastatic effect of AA were performed to lung nodule numbers in vivo metastasis mice model. MMP15, pERK1/2 and p-p38MAPK expressions were determined by immunohistochemistry. RESULTS: Our findings indicated cell proliferation and cell cycle distribution of RCC cells were not significantly influenced by AA treatment. AA suppressed cell migration, invasion and significantly down-regulated mRNA and protein expression of MMP-15 (Matrix Metallopeptidase-15). Activation of ERK1/2 and p38MAPK were inhibited with AA, whereas combined AA with siRNA-ERK or siRNA-p38MAPK markedly reduced the metastatic effect and decreased MMP-15 expression in 786-O and A498 cells. Finally, AA significantly reduced the lung metastasis formation and metastasis-related proteins of human 786-O cells in vivo metastasis mice model. CONCLUSION: AA inhibits the metastatic properties of RCC cells via inhibition of the p-ERK/p-p38MAPK axis and the subsequent down-regulation of MMP-15 in vitro and in vivo. Further study of AA as a potential anti-metastatic agent for RCC is warranted.

Causative organisms and antimicrobial susceptibility in jaundiced infants with significant bacteriuria.

BACKGROUND: Jaundice may be one of the first signs of urinary tract infection (UTI) in infants. The most common pathogen is Escherichia coli. Currently recommended antibiotic treatment for neonatal UTI is ampicillin and an aminoglycoside. Recently, increasing ampicillin and gentamicin resistance in strains of E. coli has been isolated. The aim of this study was to determine causative organisms and antimicrobial susceptibility in jaundiced infants with significant bacteriuria (SB). METHODS: We evaluated admitted afebrile, asymptomatic infants younger than 1-month old with hyperbilirubinemia (total bilirubin >15 mg/dl) requiring phototherapy between January 2011 and December 2015. A total of 615 asymptomatic jaundiced infants were enrolled. Urinalysis and urine cultures were performed on all jaundiced infants. A urine culture was defined as SB if a single pathogen with more than 105-colony forming units per milliliter (CFU/ml) by sterile urinary collection bag or 104 CFU/ml by catheterization was isolated. RESULTS: A total of 88 (14.3%) of 615 asymptomatic jaundiced infants had positive urinary culture. E coli was the most common cultured bacteria (40 cases, [45.5%]). Enterococcus faecalis was the second most common bacteria (17 cases, [19.3%]). Seven cases (8.0%) of Streptococcus agalactiae and six cases (6.8%) of Klebsiella pneumoniae were also identified. Ampicillin sensitivity was found in 22.5% of E. coli infections, gentamicin sensitivity was found in 84.2%, and extended-spectrum ß-lactamases were found in 7.5%. CONCLUSION: E. coli was the most common causative organism for infants with SB. We suggest modifying current empiric antibiotics by changing gentamicin to amikacin for neonatal Gram-negative bacterial infections.

Magnolol Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells through JNK1/2 and p38 Pathways.

Magnolol is a natural compound extracted from Chinese herbal medicine and can induce apoptosis in numerous types of cancer cells. However, the molecular mechanisms of magnolol in oral cancer are still unclear. In this study, we investigated the anti-cancer effects and underlying mechanisms of magnolol in human oral cancer cell lines. Our results exhibited that magnolol inhibited the cell proliferation via inducing the sub-G1 phase and cell apoptosis of HSC-3 and SCC-9 cells. The human apoptosis array and Western blot assay showed that magnolol increased the expression of cleaved caspase-3 proteins and heme oxygenase-1 (HO-1). Moreover, we proved that magnolol induces apoptosis in oral cancer cell lines via the c-Jun N-terminal kinase (JNK)1/2 and p38 pathways. Overall, the current study supports the role for magnolol as a therapeutic approach for oral cancer through JNK1/2- and p38-mediated caspase activation.

Melatonin Inhibits Osteoclastogenesis and Osteolytic Bone Metastasis: Implications for Osteoporosis.

Osteoblasts and osteoclasts are major cellular components in the bone microenvironment and they play a key role in the bone turnover cycle. Many risk factors interfere with this cycle and contribute to bone-wasting diseases that progressively destroy bone and markedly reduce quality of life. Melatonin (N-acetyl-5-methoxy-tryptamine) has demonstrated intriguing therapeutic potential in the bone microenvironment, with reported effects that include the regulation of bone metabolism, acceleration of osteoblastogenesis, inhibition of osteoclastogenesis and the induction of apoptosis in mature osteoclasts, as well as the suppression of osteolytic bone metastasis. This review aims to shed light on molecular and clinical evidence that points to possibilities of melatonin for the treatment of both osteoporosis and osteolytic bone metastasis. It appears that the therapeutic qualities of melatonin supplementation may enable existing antiresorptive osteoporotic drugs to treat osteolytic metastasis.

Dihydromyricetin suppresses cell metastasis in human osteosarcoma through SP-1- and NF-κB-modulated urokinase plasminogen activator inhibition.

BACKGROUND: Metastasis caused a decline in the 5-years survival rate of osteosarcoma. Therefore, developing new targeted therapeutics for osteosarcoma treatment is imperative. Dihydromyricetin (DHM) has several physiological functions: it counteracts inflammation, oxidation, and antitumor properties. However, the effects of DHM on osteosarcoma and its underlying mechanisms are still not well understood. PURPOSE: In this study, we investigated the antimetastatic properties of DHM in human osteosarcoma U-2 OS and HOS cells. METHODS: The effects of DHM (0, 25, 50, 75, and 100 µM) on cell viability, migration, and invasion were examined. Western blotting, RT-PCR, and quantitative real-time PCR (QPCR) were determined urokinase plasminogen activator (uPA) expression. The expression of transcriptional factor SP-1 and NF-κB was determined by using immunofluorescence assay, chromatin immunoprecipitation assay, and site-directed mutagenesis luciferase reporter. RESULTS: We observed that DHM suppresses cell migration and invasion in osteosarcoma cell lines. In addition, DHM inhibits metastasis by downregulating urokinase plasminogen activator (uPA) expression. Moreover, real-time polymerase chain reaction and promoter activity assays revealed that DHM decreased uPA expression at transcription levels. Furthermore, the inhibition of uPA expression was associated with the suppression of SP-1 and NF-κB, which bind to the uPA promoter. Regardless of blocking or inducing the extracellular signal-regulated kinase (ERK) pathway, we verified that the DHM-related suppression of uPA and cell metastasis occurred through the p-ERK pathway. CONCLUSION: We are the first study to propose that DHM suppresses osteosarcoma metastasis through the ERK pathway and through the suppression of SP-1 and NF-κB to inhibit downstream uPA expression. DHM is a potential therapeutic agent for antimetastatic therapy against osteosarcoma.

Effects of NAC and Gallic Acid on the Proliferation Inhibition and Induced Death of Lung Cancer Cells with Different Antioxidant Capacities.

N-acetylcysteine (NAC) is a recognized antioxidant in culture studies and treatments for oxidative stress-related diseases, but in some cases, NAC is a pro-oxidant. To study the effect of NAC on cell proliferation in the presence or absence of ROS stress, we used the stable ROS generator gallic acid (GA) to treat CL1-0 lung cancer cell models with different antioxidant activities. Different antioxidant activities were achieved through the ectopic expression of different PERP-428 single nucleotide polymorphisms. GA increased ROS levels in CL1-0/PERP-428C cells and caused cell death but had no effect on CL1-0/PERP-428G cells within 24 h. We found that 0.1 mM NAC eliminated GA-induced growth inhibition, but 0.5 mM NAC enhanced GA-induced CL1-0/PERP-428C cell death. However, in the absence of GA, NAC exceeding 2 mM inhibited the growth of CL1-0/PERP-428G cells more significantly than that of CL1-0/PERP-428C cells. Without GA, NAC has an antioxidant effect. Under GA-induced ROS stress, NAC may have pro-oxidant effects. Each cell type has a unique range of ROS levels for survival. The levels of ROS in the cell determines the sensitivity of the cell to an antioxidant or pro-oxidant. Cells with different antioxidant capacities were used to show that the intracellular ROS level affects NAC function and provides valuable information for the adjuvant clinical application of NAC.

Tricetin Suppresses Migration and Presenilin-1 Expression of Nasopharyngeal Carcinoma through Akt/GSK-3ß Pathway.

Lymph node migration results in poor prognoses for nasopharyngeal carcinoma (NPC) patients. Tricetin, a flavonoid derivative, regulates tumorigenesis activity through its antiproliferative and antimetastatic properties. However, the molecular mechanism of tricetin affecting the migration and invasion of NPC cells remains poorly understood. In this paper, we examined the antimetastatic properties of tricetin in human NPC cells. Our results demonstrated that tricetin at noncytotoxic concentrations (0-80 3M) noticeably reduced the migration and invasion of NPC cells (HONE-1, NPC-39, and NPC-BM). Moreover, tricetin suppressed the indicative protease, presenilin-1 (PS-1), as indicated by protease array. PS-1 was transcriptionally inhibited via the Akt signaling pathway but not mitogen-activated protein kinase pathways, such as the JNK, p38, and ERK1/2 pathways. In addition to upregulating GSK-3[Formula: see text] phosphorylation through Akt suppression, tricetin may downregulate the activity of PS-1. Overall, our study provides new insight into the role of tricetin-induced molecular regulation in the suppression of NPC metastasis and suggests that tricetin has prospective therapeutic applications for patients with NPC.

Dioscorea nipponica Makino suppresses TPA-induced migration and invasion through inhibition of matrix metalloproteinase-9 in human cervical cancer cells.

Dioscorea nipponica Makino has been used for the treatment of chronic bronchitis, rheumatoid arthritis, cough, and asthma. Several studies have established the antitumor effect of D. nipponica Makino extract (DNE). However, no investigations have considered the antimetastatic potential of DNE in cervical cancer cells. The present study examined the effects of DNE on cervical cancer cells treated with 12-O-tetradecanoylphorbol-13-acetate and characterized the possible molecular mechanisms. MTT assay results indicated that DNE exhibited very low cytotoxicity, and DNE significantly reduced the invasion and migration abilities of cervical cancer cells. Gelatin zymography analysis revealed that DNE significantly inhibited matrix metalloproteinase-9 (MMP-9) activity. Reverse transcription-polymerase chain reaction assay results revealed that DNE treatment inhibited the MMP-9 mRNA levels of HeLa and SiHa cells. Western blot results revealed that DNE significantly diminished the ERK1/2 phosphorylation. In conclusion, we revealed that the antimetastatic effects of DNE on cervical cancer cells are due to its inhibition of MMP-9 expression through the ERK1/2 pathway.

New insights into antimetastatic signaling pathways of melatonin in skeletomuscular sarcoma of childhood and adolescence.

Melatonin is an indole produced by the pineal gland at night under normal light or dark conditions, and its levels, which are higher in children than in adults, begin to decrease prior to the onset of puberty and continue to decline thereafter. Apart from circadian regulatory actions, melatonin has significant apoptotic, angiogenic, oncostatic, and antiproliferative effects on various cancer cells. Particularly, the ability of melatonin to inhibit skeletomuscular sarcoma, which most commonly affects children, teenagers, and young adults, is substantial. In the past few decades, the vast majority of references have focused on the concept of epithelial-mesenchymal transition involvement in invasion and migration to allow carcinoma cells to dissociate from each other and to degrade the extracellular matrix. Recently, researchers have applied this idea to sarcoma cells of mesenchymal origin, e.g., osteosarcoma and Ewing sarcoma, with their ability to initiate the invasion-metastasis cascade. Similarly, interest of the effects of melatonin has shifted from carcinomas to sarcomas. Herein, in this state-of-the-art review, we compiled the knowledge related to the molecular mechanism of antimetastatic actions of melatonin on skeletomuscular sarcoma as in childhood and during adolescence. Utilization of melatonin as an adjuvant with chemotherapeutic drugs for synergy and fortification of the antimetastatic effects for the reinforcement of therapeutic actions are considered.

Erianin Induces Apoptosis and Autophagy in Oral Squamous Cell Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths worldwide. It has a very poor prognosis with over a 5-year survival rate of only 50%. Thus, it is important to identify effective therapeutic interventions against oral cancer. Apoptosis and autophagy have reported genetically regulated in physiology and diseases, which close relationship. Many natural compound study objects anticancer effect have been studied between apoptosis and autophagy relationship. The present study was designed to evaluate the effect of erianin on human oral cancer cell proliferation. Results of the study revealed that treatment with erianin significantly reduced the viability of different OSCC cell lines. Erianin exerted its cytotoxic effect by inducing cell cycle arrest and caspase-dependent apoptotic pathways. Both intrinsic and extrinsic pathways were found to be involved in erianin-mediated cell death. In addition, treatment with erianin also increased autophagy in OSCC cells. With further analysis, it was found that erianin induced both apoptosis and autophagy by regulating MAPK signaling pathways. Taken together, our study indicates that erianin plays an important role in reducing oral cancer cell viability, and thus, can be considered as a potential anticancer agent.

Salvianolic acid A suppresses MMP-2 expression and restrains cancer cell invasion through ERK signaling in human nasopharyngeal carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge, as known as Danshen, has used for the prevention and treatment of cardiovascular diseases clinically and anti-cancer activities. Salvianolic acid A (SAA), one of the most abundant ingredients, hydrophilic derivatives of Salvia miltiorrhiza Bunge, exerts a variety of pharmacological actions, such as anti-oxidative, anti-inflammatory and anti-cancer activities. However, the impact of SAA on nasopharyngeal carcinoma (NPC) invasion and metastasis remains unexplored. AIM OF THE STUDY: To investigate the potential of SAA to prevent migration and invasion on NPC cell. MATERIALS AND METHODS: MTT assay and Boyden chamber assay were performed to determine cell proliferation, migration and invasion abilities, respectively. The activity and protein expression of matrix metalloproteinase-2 (MMP-2) were determined by gelatin zymography and western blotting. RESULTS: Here, we showed that SAA considerably suppressed the migrative and invasive activity of human NPC cells but not rendered cytotoxicity. In SAA-treated NPC cells, the activity and expression of matrix metalloproteinase-2 (MMP-2), a key regulator of cancer cell invasion, were reduced. Additionally, the presence of high concentrations of SAA dramatically abolished the activation of focal adhesion kinase (FAK) and moderately inhibited the phosphorylation of Src and ERK in NPC cells. CONCLUSIONS: Our results demonstrated that SAA inhibited the migration and invasion of NPC cells, accompanied by downregulation of MMP-2 and inactivation of FAK, Src, and ERK pathways. These findings indicate a usefulness of SAA on restraining NPC invasion and metastasis.

Molecular and Cellular Mechanisms of Melatonin in Osteosarcoma.

Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11-15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in bone growth and the peak age distribution of osteosarcoma during puberty, so melatonin has been utilized as an adjunct to chemotherapy to improve the quality of life and clinical outcomes. While a large amount of research has been conducted to understand the complex pleiotropic functions and the molecular and cellular actions elicited by melatonin in various types of cancers, a few review reports have focused on osteosarcoma. Herein, we summarized the anti-osteosarcoma effects of melatonin and its underlying molecular mechanisms to illustrate the known significance of melatonin in osteosarcoma and to address cellular signaling pathways of melatonin in vitro and in animal models. Even in the same kind of osteosarcoma, melatonin has been sparingly investigated to counteract tumor growth, apoptosis, and metastasis through different mechanisms, depending on different cell lines. We highlighted the underlying mechanism of anti-osteosarcoma properties evoked by melatonin, including antioxidant activity, anti-proliferation, induction of apoptosis, and the inhibition of invasion and metastasis. Moreover, we discussed the drug synergy effects of the role of melatonin involved and the method to fortify the anti-cancer effects on osteosarcoma. As a potential therapeutic agent, melatonin is safe for children and adolescents and is a promising candidate for an adjuvant by reinforcing the therapeutic effects and abolishing the unwanted consequences of chemotherapies.

The Potential of Chinese Herbal Medicines in the Treatment of Cervical Cancer.

Cervical cancer is a global health issue and places a considerable economic and medical burden on society. Thus, a concerted effort to improve the treatment of cervical cancer is warranted. Although several treatment options are currently available for treating patients with cervical cancer, such as chemoradiation and neoadjuvant or adjuvant chemotherapy, more aggressive systemic therapies and newer therapeutic agents are under investigation. Medicinal herbs have long been used to treat diseases. In this review, we summarize studies analyzing the antitumor effects and underlying mechanisms of Chinese herbal medicines, including the effects of crude extracts and compounds in vitro or in animal models for inducing apoptosis and inhibiting invasion or metastasis. Chinese herbal medicines with therapeutic targeting, such as those that interfere with tumor growth and progression in cervical cancer, have been widely investigated. To apply Chinese herbal medicine in the treatment of cervical cancer, adequate clinical studies are required to confirm its clinical safety and efficiency. Further investigations focused on the purification, pharmacokinetics, and identification of compounds from Chinese herbal medicines in cervical cancer treatment are necessary to achieve the aforementioned treatment goals.

Duchesnea indica extract attenuates oral cancer cells metastatic potential through the inhibition of the matrix metalloproteinase-2 activity by down-regulating the MEK/ERK pathway.

BACKGROUND: Duchesnea indica (Andr.) Focke, an herb in folk medicine used extensively in traditional Chinese medicine, has cytostatic properties as well as antioxidant and antimetastasis activities in various cancer cells. However, the effects and underlying mechanisms of Duchesnea indica extracts (DIEs) on human oral squamous cell carcinoma (OSCC) metastases remain unclear. PURPOSE: In this study, we posit the hypothesis that DIE possesses antimetastatic effects on human OSCC cells. METHODS: The effects of DIE on cell viability, motility, migration, and invasion were investigated. Gelatin zymography, Western blotting, migration and invasion assays were used to further study the underlying mechanisms involved in the antimetastatic effects of DIE in OSCC cells. RESULTS: The results from MTT assay revealed that DIE did not affect the cell viability of OSCC cells. Moreover, DIE significantly attenuated OSCC cells' motility, migration, and invasion by reducing the MMP-2 protein expression and MMP-2 activity in a dose-dependent manner. In addition, DIE reduced the phosphorylation of both ERK1/2 and its upstream kinase but had no effect on the phosphorylation of p38 and JNK. CONCLUSION: DIE triggers the antimetastatic activity in OSCC cells by suppressing the MMP-2 activity via the MEK/ERK signaling pathways. Therefore, these findings are promising for the use of DIE antimetastatic activity in oral cancer metastasis treatment.

Geraniin inhibits oral cancer cell migration by suppressing matrix metalloproteinase-2 activation through the FAK/Src and ERK pathways.

Geraniin has been reported to have numerous biological activities, including antiviral, antihypertensive, antihyperglycaemic, liver protective, antidiabetic, and apoptotic activities. However, the anti-migration effects of geraniin on oral cancer remain elusive. In this study, we revealed the potential antitumor mechanisms of geraniin through the inhibition of the migration and invasion of human oral cancer cell lines SCC-9 and SCC-14. The results of gelatin zymography and Western blot assays revealed that geraniin significantly reduced the activity and expression of matrix metalloproteinase-2 (MMP-2) of oral cancer cells in a concentration-dependent manner. Furthermore, geraniin potently suppressed the phosphorylation of focal adhesion kinase (FAK), Src, and extracellular signal-regulated kinase (ERK)1/2 but did not affect the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase 1/2. Moreover, blocking the MAPK/ERK1/2 pathway significantly enhanced the anti-migration ability of geraniin in oral cancer cells. In conclusion, we demonstrated that geraniin inhibits the motility of SCC-9 and SCC-14 cells in vitro through a molecular mechanism that involves the attenuation of MMP-2 expression and activity mediated by decreased FAK/Src and ERK1/2 pathways.

Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells.

BACKGROUND: Phloretin, a dihydrochalcone flavonoid, possesses anti-inflammatory activity and inhibits the growth of various cancers. However, the flavonoid's effect on cervical cancer metastasis and angiogenesis remains unknown. PURPOSE: In this study, we provide molecular evidence associated with the antimetastatic and antiangiogenic effects of phloretin. METHODS: In this study, the anti-invasive effect of phloretin (0-60 µM) in cervical cancer cells was evaluated using the Matrigel invasion assay, gelatin zymography, cell-matrix adhesion assay, wound healing assay, and Western blotting. Antiangiogenic potential of phloretin (0-100 µM) was assessed by the Matrigel tube formation assay. The in vivo antitumor effect of phloretin (10 or 20 mg/kg) was fed by oral gavage and determined using subcutaneous inoculation and tail vein injection in immunodeficient nude mice. RESULTS: Phloretin (60 µM) showed marked suppression of invasion and migration through downregulation of matrix metalloproteinase (MMP)-2, MMP-3, and cathepsin S in human SiHa cervical cancer cells. Phloretin (60 µM) reversed the epithelial-mesenchymal transition induced by transforming growth factor-ß1 and downregulated mesenchymal markers, such as fibronectin, vimentin, and RhoA. Phloretin (100 µM) treatment significantly inhibited the aldehyde dehydrogenase 1 activity of SiHa cells, reduced the self-renewal properties and stemness signatures of CD44 and Sox-2 in sphere-forming cervical cancer-derived tumor-initiating cells, and inhibited the invasion, MMP-2 activity, and tube formation capacity of human umbilical vein endothelial cells. The ability of phloretin (20 mg/kg) to suppress lung metastasis and tumor growth in SiHa cells was evidenced by tail vein injection and subcutaneous inoculation in a tumor xenograft model. CONCLUSION: In summary, the findings indicate that phloretin inhibits the metastatic and angiogenic abilities and cancer stemness of SiHa cells, thereby suggesting that this flavonoid is a promising therapeutic agent for the treatment of human cervical cancer cells.